In new research led by researchers at UCL and the University of Oxford, a new form of CAR T-cell therapy has been designed to find and destroy cancer-driving stem cells that cause a group of blood cancers known as myeloproliferative neoplasms (MPNs), while leaving healthy blood cells intact.
MPN is a chronic blood cancer caused by mutations in the DNA of blood stem cells. Over time, some patients progress to myelofibrosis, a serious condition characterized by scarring of the bone marrow and anemia.
In approximately 1 in 5 cases, the disease progresses to an aggressive leukemia-like stage, which can prolong survival by several months. For most patients, no curative treatment is available.
CAR T-cell therapy works by reprogramming a patient’s own immune cells to target specific cells in the body and has already been used successfully as a treatment for other blood cancers. In this study, scientific translational medicineThe genetically engineered cells were designed to recognize a mutation called CALR, which is found in about a third of MPN patients.
Using patient samples, a model that replicates human bone marrow in the lab, and studies in mice, the researchers showed that CAR T cells can precisely kill cancer cells with CALR mutations without harming other blood cells.
A Phase I clinical trial is planned at UCLH, with the aim of starting within the next 1-2 years, subject to funding and regulatory approval.
MPN can be devastating, especially when it progresses to myelofibrosis, and current drugs are often unable to eliminate the cancer stem cells that cause the disease. What’s interesting about this approach is its accuracy. CALR mutations produce abnormal proteins on the surface of these cells, giving them distinct targets. CAR T-cell therapy technology can exploit this vulnerability and significantly boost the immune system to eradicate these cells and restore normal blood production.
Our goal is to turn this into a first-in-human clinical trial and ultimately a treatment that can selectively eliminate the root of the disease. If successful, it could go beyond symptom control and offer patients a path toward deeper and longer-lasting remission, with the hope of restoring healthy blood production. ”
Dr. Alex Lampotas, first author, UCL Cancer Institute
Current treatments for MPN include JAK inhibitors, which can quell excessive immune responses and slow disease progression, but they do not eliminate the cancer stem cells that drive the disease. Most patients eventually stop responding to these drugs.
Bone marrow transplantation is potentially curative, but is only suitable for a small number of patients, and treatment-related mortality can reach up to 40%.
CALR mutations are found on the surface of cancer stem cells and act like a visible flag that can potentially be recognized by the immune system. The research team engineered CAR T cells to detect this flag, which can kill CALR cancer cells with high potency and selectivity.
In patients whose disease progressed to an accelerated phase, CAR T cells initially did less work because levels of the target protein were lower. Researchers have found that eltrombopag, a drug used clinically for some platelet and blood conditions, increases the amount of targets on cancer cells and may improve killing of CAR T cells.
The research team also tested the study using 3D mini-bone marrow grown in the lab. Using a bone marrow model seeded with real myelofibrosis cells, the research team was able to show that CAR T cells can even migrate into severe scar tissue (fibrosis) and kill cancer cells.
In mouse models, CAR T cells targeting CALR also controlled leukemia proliferation and significantly prolonged survival.
One of the study’s senior authors, Professor Beth Psaila from the University of Oxford’s MRC Weatherall Institute for Molecular Medicine and the Ludwig Institute for Cancer Research, said: “Our model is designed to reproduce the real-life conditions in which these cancers grow, including fibrosis and complex tissue architecture, where treatments can fail in the gap between the lab and the clinic. CAR “It was very encouraging to see T cells finding and killing cancer cells within fibrotic bone marrow organoids.” step.
“Equally important, this model allows us to test not only whether a treatment is effective, but also how it works cell by cell in human tissue. We hope this platform will facilitate the development of safer and more effective immunotherapies for myelofibrosis and other blood cancers.”
Although MPN is classified as rare, approximately 4,000 people are diagnosed with MPN each year in the UK (approximately 8 in 100,000)*. The CALR mutation group accounts for about one-third of cases, with about 600 to 900 newly diagnosed patients per year, and many more people already living with the disease.
The team is currently seeking funding for the planned clinical trials and is working with regulators and the MHRA. Researchers predict that if early clinical results are promising, access to potentially transformative treatments could become even wider by the early to mid-2030s.
sauce:
university college london
Reference magazines:
Lampotas, A. Others. (2026). CAR T cell therapy selectively depletes disease-causing mutant calreticulin cells in xenografts and human organoid models of myelofibrosis. scientific translational medicine. DOI: 10.1126/scitranslmed.adz3553. https://www.science.org/doi/10.1126/scitranslmed.adz3553
